The central theme of this application is to clarify the role of regulatory T cells (Treg) in autoimmune diseases and explore their potential as therapeutic agents. Toward this end, we propose a tightly focused, fully integrated set of laboratory and clinical studies. Specifically, our proposal includes: Clinical Center (David Wofsy, PI): Investigators involved in this application have extensive experience in the conduct of clinical trials in diverse autoimmune diseases. Two concept proposals are presented. Protocol 1 is a phase Ib/lla trial of anti-CD20 plus cyclophosphamide (IVC) as induction therapy in patients with active lupus nephritis. It will test the hypothesis that the use of IVC in conjunction with anti-CD20 will promote emergence of Tregs and thereby provide sustained clinical benefit. Protocol 2 is a phase II trial of imatinib (Gleevec(r)) in patients with new-onset type I diabetes mellitus. This trial is based on extensive pre-clinical work in our own laboratories. It will test the hypothesis that imatinib eliminates activated autoreactive T cells and thereby restores tolerance to islet antigens. Project 1 - Genetically-Engineered Antigen-Specific Treqs to Treat Autoimmunity (Jeffrey Bluestone, PI): The principal goals of this project are: (i) to develop engineered antigen-specific Tregs by introducing autoreactive T cell receptors (TCRs) and other therapeutic genes, (ii) to assess the mechanisms and safety of cellular therapy with engineered Tregs;an (iii) to generate large quantities of autoreactive engineered Tregs capable of suppressing pathogenic autoreactive T cell responses. Project 2 - Stability and Plasticity of Treqs (Abul Abbas, PI): This project tests the hypothesis that effector T cells and Treg are not fixed lineages, but can be converted by changes in their environment. By defining the mechanisms underlying plasticity and stability, we seek to develop means to optimize cellular therapy. Pilot Project - Isolation. Expansion, and Function of Tregs in SLE (David Daikh, PI): The principal goals of this project are;(i) to determine the ability to activate and expand Tregs purified from patients with SLE;and (ii) to evaluate the functional potential of these Tregs as a foundation for potential treatment of lupus with expanded autologous Tregs. The broad aim of the ACE program at UCSF is to work collaboratively with other ACE sites to translate advances in immunology and molecular biology into practical, safe, and effective therapies for people with autoimmune diseases. Within this umbrella, the UCSF site will focus on interrelated aspects of Treg biology and potential clinical applications through a highly coordinated set of clinical and laboratory studies designed to bring Treg therapy from bench to bedside. CLINICAL COMPONENT (WOFSY, D) CLINICAL COMPONENT (provided by applicant): The University of California, San Francisco (UCSF) conducts clinical trials in a wide range of autoimmune diseases. This proposal focuses primarily on three of these diseases (systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes mellitus), but we also describe active programs in several other autoimmune diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and scleroderma. Two concept proposals for clinical trials are presented to demonstrate our interests and our ability to develop collaborative multicenter clinical trials for patients with autoimmune diseases. The two proposed clinical trials are: Protocol 1 is a randomized, double-blind, phase Ib/IIa trial of anti-CD20 plus cyclophosphamide (IVC) as induction therapy in patients with active lupus nephritis. This trial is based on extensive, but uncontrolled, clinical series indicating that brief induction therapy with anti-CD20 plus IVC is effective in lupus nephritis and, moreover, that this combination may offer the potential to minimize chronic immune suppression. It will test the hypothesis that the use of IVC in conjunction with anti-CD20 will promote emergence of Tregs and thereby provide sustained clinical benefit. Protocol 2 is a randomized, double-blind, phase II trial of imatinib (Gleevec(r)) in patients with new-onset type I diabetes mellitus (T1DM). This trial is based on extensive pre-clinical work in our own laboratories indicating that imatinib is effective in diabetes-prone NOD mice. This trial will test the hypothesis that imatinib eliminates activated autoreactive T cells and thereby restores tolerance to islet antigens in T1DM patients. The ACE program at UCSF seeks to work collaboratively with other ACE sites to translate advances in immunology and molecular biology into practical, safe, and effective therapies for people with autoimmune diseases. Our programs across a broad range of diseases provide a strong foundation for such collaborations, toward this end, we have put forward two concept proposals that address important unanswered questions that could become the focus of ACE trials and mechanistic studies.